Overt inflammation at the site of a wound or infection has been well characterized at the level of tissue pathology, cell biology, microbiology, biochemistry and molecular biology. What we now understand is that these same processes at a lower level produce a state of microinflammation that presents very few clinical symptoms but that is a human health concern. The conditions that predispose to microinflammation are a consequence of both genetics and aging, so that microinflammation is more common among the elderly. The conditions include reduced vasoreactivity and increased response to environmental toxins. The results of a challenge to these conditions are an exaggerated vasodilation, influx of inflammatory cells and release of cytotoxins. This can be associated with erythema and pain, but often this cycle of challenge and response is chronic and presents symptoms only at later stages. Microinflammation of this type may be responsible for much of heart disease, Alzheimer's disease, arthritis, cancer and many other chronic diseases which finally manifest themselves in the elderly.
Important mediators of both acute and microinflammation are prostaglandins (PG). PG synthesis from the precursor arachidonic acid is controlled by the cyclo-oxygenases (COX) enzymes. The family of PG signals many responses, such as vasodilation, and activation of inflammatory cells. A basal level of PG is maintained by COX-1, which is necessary for normal cell metabolism. In response to noxious stimuli, COX-2 is induced and activated, producing a superabundance of PG that leads to many inflammatory responses. Unfortunately, as we age, the resting level of COX-2 increases, and therefore the production of PG in response to a stimulus also increases.
Modulators of PG are widely sought after because of the enormous market for their effects. Very successful new pharmaceutical chemical entities have been commercialized that selectively inhibit COX-2 and thereby inhibit the inflammatory responses characteristic of aging. These modulators should be well-defined, consistent and selective in their actions to avoid side-effects, especially since they may be used over long periods of time and by the elderly.
Botanical extracts prepared from plants are believed by some members of the scientific community to influence PG production and to have anti-inflammatory effects. An example is the extract produced from the Evodia rutaecarpa fruit, which is known in traditional Chinese medicine as Wu-Chu-Yu. The extract alone and combined with other botanical extracts has been described as an anti-inflammatory agent, an antineoplastic agent, a skin whitening treatment, an anti-hypertensive, an extract for providing skin with wetness and increase in gloss, and a treatment for pain, among many other claims. These extracts contain many organic compounds that have been studied individually, and various effects have been attributed to the individual components, the major ones being the indolequinazoline alkaloids. These are also known as quinazolindocarboline alkaloids and in Evodia fruit they are primarily rutaecarpine, evodiamine and dehydroevodiamine. The Evodia fruit is not common or easily grown, and the relative amounts of the compounds in the extract prepared from the fruit vary greatly by the time of year, geographic location, year of the harvest, as well as the extraction and preservation method, and many other variables. All these factors have contributed to the lack of commercialization of this extract.
It is also desirable to have a convenient test system to measure the inhibition of the microinflammatory response in human skin, which generates both nitric oxide (NO) and PG, has no long-lasting effects and is not harmful to the subject. Current methods for testing inhibition of inflammation involve the use of strong irritants, such as sodium lauryl sulfate, carrageenan or Balsam of Peru. These produce vigorous and sometimes painful inflammatory reactions. Methyl nicotinate (MN) has been used to generate a flushing response as a method of diagnosing schizophrenia. Susceptibility to skin stinging has been suggested to be related to over-reaction to methyl nicotinate (Issachar et al., 1998), but this has been contradicted (Coverly et al., 1998). Methyl nicotinate induced inflammation is inhibited by inhibitors of PG (Wilkin et al, 1985).